1. Field of the Invention
The invention concerns an improvement in the treatment of humans afflicted with paralysis agitans by administration of 3,4-dihydroxyphenyl-1-alanine. More particularly, the invention concerns potentiation of 3,4-dihydroxyphenyl-1-alanine with a benzodiazepine adjuvant.
2. Description of the Prior Art
A combination of 3,4-dihydroxyphenyl-1-alanine with a tricyclic antidepressant such as 5-[3-(dimethylamino)-propyl]-10,11-dihydro-5H-dibenz[b,f]azepine and an N.sup.1 -substituted-N.sup.2 -(2,3-4-trihydroxybenzyl)-hydrazine is disclosed in U.S. Pat. No. 3,646,213 as an effective antidepressant composition.
The use of 3,4-dihydroxyphenyl-1-alanine, hydrates thereof and pharmaceutically acceptable acid addition salts thereof, to treat humans afflicted with paralysis agitans (also referred to alternatively in the literature as "shaking palsy", "Parkinsonism", "Parkinson's syndrome" and "Parkinson's disease") has been well documented; see, for example, Cotzias et al., Long-Term Effects of DOPA on Parkinsonism, 3rd Symposium on Parkinson's Disease, Edinburgh, 1968, Vol. 1, Gillingham and Donaldson, Editors, pps. 178-181, London, E. and S. Livingston, Publ. (1969); DuVoisin et al., 3rd Symposium on Parkinson's Disease, supra., pps. 185-192; Van Woert et al., N. Eng. Jour. Med., 276, 374-9, (1967) and Siegfried et al., Pharm Clin., 2, 23-6, (1969); U.S. Pat. Nos. 3,557,292 and 3,701,829. The dosage of 3,4-dihydroxyphenyl-1-alanine required to alleviate the symptoms of paralysis agitans ranges from 5 to 8 grams daily for the average adult patient. At therapeutic dosage levels, a number of undesirable peripheral side effects occur, such as for example, nausea, involuntary movements (choreiform nods, twitchs, grimaces, weaving gait and shuffles), somnolence, depression and increased libido.
Cash, et al. disclosed in U.S. Pat. No. 3,729,563 that the high doses of 3,4-dihydroxy-1-alanine required to treat Parkinsonism could be reduced by administering it in conjunction with doses of gallic acid. Gallic acid and its derivatives themselves have the property of alleviating involuntary muscle activity for short periods of time.
Siegfried et al., Ger. Med. Monthly, 15, 315, (1970), and Siegfried et al., supra., reported that the dosage of 3,4-dihydroxyphenyl-1-alanine required to alleviate the akinesiatic symptoms of paralysis agitans could be reduced to as little as one-tenth of the usual dosage by administering it in conjunction with a decarboxylase inhibitor (see also J.A.M.A., Vol. 212, No. 11, pg. 1791; U.S. Pat. Nos. 3,557,292 and 3,701,829). Such inhibitors generally block the normal metabolic conversion of dopamine (3,4-dihydroxyphenethylamine) in brain tissue to norepinephrine, thus elevating dopamine levels. Although a number of the peripheral side effects of 3,4-dihydroxyphenyl-1-alanine disappear with reduced dosage levels, the combination with a decarboxylase inhibitor does not provide a completely satisfactory solution for treating paralysis agitans. For example, symptoms of akathisia tend to worsen and tremors seem to become exaggerated (Siegfried et al., Pharm. Clin., supra.). The decarboxylase inhibitors are also not without their limitations in use. For example, they are generally not advisably administered to patients having a history of cardiovascular disease. Since a high proportion of patients afflicted with paralysis agitans also have a history of arteriosclerosis the use of decarboxylase inhibitors to reduce dosage levels of 3,4-dihydroxyphenyl-1-alanine is limited.
We have found that the anti-paralysis agitans symptom activity of 3,4-dihydroxyphenyl-1-alanine is potentiated when administered concurrently with a benzodiazepine compound. As a result, the required dose of 3,4-dihydroxyphenyl-1-alanine for alleviating symptoms of paralysis agitans can be reduced by from 25 to 75 percent with the advantage of reduced side effects.
Our finding is surprising since the benzodiazepines do not themselves bring about a lessening of symptoms of paralysis agitans. Furthermore, the benzodiazepines are not known to inhibit the normal metabolism of dopamine, as occurs with the decarboxylase inhibitors.
The method and compositions of our invention are particularly advantageous because the benzodiazepines are generally not contraindicated in the presence of a history of cardiovascular disease. In addition, we have found the combination of 3,4-dihydroxyphenyl-1-alanine and benzodiazepine to be less toxic than the combination of 3,4-dihydroxyphenyl-1-alanine and a decarboxylase inhibitor such as, for example, imipramine or tranylcypromine or an antidepressant; see for example, Proctor et al., Arch. Int. Pharm., 163, 87, (1966) reporting on the potentiation of lethality of 3,4-dihydroxyphenyl-1-alanine when administered to aggregated mice with monoamine oxidase inhibitors and a similar result obtained when 3,4-dihydroxyphenyl-1-alanine was administered with an antidepressant [Johnson et al., Current Ther. Res., 12, 402, (1970)].